CD97, a membrane protein expressed at high levels on inflammatory cells and some carcinomas, is a member of the adhesion G protein coupled receptor (GPCR) family. This family has a fascinating, bipartite adhesion/signaling structure, but almost nothing is known about the biological functions and mechanisms of signaling among the 33 known members. To date, we have analyzed firstly, the cell autonomous function(s) of CD97, using CD97 null mice, and secondly, the role of the extracellular adhesive domain of CD97 as a counter-receptor, using the purified extracellular domain as a biological probe. We have determined that CD97 functions in leukocyte migration, at least in part, by cross-regulating chemokine receptor responses. In addition, we have discovered that the CD97 extracellular domain binds with high affinity to angiogenic integrins, a5b1, avb3, and avb5, leading to increased endothelial cell migration and invasion in vitro and angiogenesis in vivo. Thus, CD97 and specific integrins are counter-receptors that may mutually transduce signals. An important question to be addressed is whether after adhesive binding, the relevant integrins will activate signaling via the CD97 GPCR and if so, how such signals are related to the identified function of leukocyte migration.